The gonadotropin hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate the fundamental reproductive processes, such as ovarian release and gamete maturation. LHRH released from the hypothalamus binds to a receptor on the pituitary gland causing the release of gonadotropin hormones. The ongoing system of feedback plays a major role in regulating the synthesis of the steroidal reproductive hormones from the gonads. ie. estrogen and progesterone in females and testosterone in males. Consequently, controlling the pulsatile release of LHRH provides an avenue for the design of novel compounds useful in treating various conditions related to dysfunction of the reproductive cycle and hormone dependent diseases.
Natural mammalian releasing hormone LHRH isolated and purified from porcine and human hypothalamus has been characterized as having the sequence:
(pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2 PA1 (a) alkyl, PA1 (b) cycloalkyl, PA1 (c) aryl, PA1 (d) cyano, PA1 (e) --(CH.sub.2).sub.q --R.sub.4, wherein q is 0 to 10, PA1 (f) -cycloalkyl-R.sub.5, and PA1 (g) -aryl-R.sub.5 ; PA1 (a) alkyl, PA1 (b) hydrogen, PA1 (c) alkoxycarbonyl, PA1 (d) hydroxymethyl, and PA1 (e) --(CH.sub.2).sub.q --R.sub.4, wherein q is 0 to 10; PA1 (a) alkyl, PA1 (b) alkoxy, PA1 (c) aryl, PA1 (d) aryloxy, PA1 (e) cyano, PA1 (f) cycloalkyl, PA1 (g) hydroxy, PA1 (h) halogen, PA1 (i) phthalimido, PA1 (j) -cycloalkyl-R.sub.5, PA1 (k) -aryl-R.sub.5, and PA1 (l) -NR.sub.6 R.sub.7 ; PA1 (a) alkyl, PA1 (b) alkoxy, PA1 (c) cyano, PA1 (d) hydroxy, PA1 (e) halogen, PA1 (f) trifluoromethyl, and PA1 (g) --(CH.sub.2).sub.q --NR.sub.6 R.sub.7, wherein q is 0 to 10; PA1 (a) hydrogen, PA1 (b) alkyl, PA1 (c) cycloalkyl, and PA1 (d) aryl, or PA1 (a) alkyl, PA1 (b) aryl, and PA1 (c) heterocycle; PA1 (a) hydrogen, PA1 (b) halogen, PA1 (c) alkoxy, PA1 (d) alkyl, and PA1 (e) trifluoromethyl; and PA1 (a) hydrogen, PA1 (b) hydroxy, PA1 (c) alkyl, PA1 (d) alkoxy, PA1 (e) alkoxycarbonyl, PA1 (f) nitro, PA1 (g) N-acyl, PA1 (h) halogen, and PA1 (i) trifluoromethyl, or
as described in A. V. Schally, Science, 202:6 (1978). Substitutions and derivatizations of amino acyl residues have been developed to achieve novel compounds useful in treating various disorders related to mammalian reproductive systems. Some derivatives of natural compounds have been shown to exhibit activity as LHRH agonists or as antagonists of LHRH.
Synthetic analogs evidencing activity in modulating LHRH secretion typically comprise peptides of naturally-occurring or non-naturally occurring amino acid residues. Peptide LHRH antagonists characterized by substitution of the nitrogen atom of at least one amide bond are described in U.S. Pat. No. 5,110,904, and U.S. Pat. No. 5,502,035.
Truncated peptide compounds developed as a series of smaller peptide analogs also exhibit biological activity and afford the added advantage of possibly improving oral bioavailability. "Pseudo" peptide compounds, see for example U.S. Pat. No. 5,140,009, are recognized LHRH antagonists. Reduced-size pentapeptides LHRH antagonists are described in pending U.S. application Ser. No. 132,999. Pending application U.S. Ser. No. 133,055 discloses heptapeptide analogs which provide active compounds truncated from the C-terminus of a decapeptide antagonist sequence.
Non-peptide heterocyclic reproductive hormone regulators have been reported in the literature, see for example, WO 95/29900 and WO 97/21704. Macrolide LHRH antagonists are described in the pending U.S. application Ser. No. 049,963; see also pending U.S. application Ser. No. 140,805. European Patent EP 0712845 discloses amine compounds exhibiting LHRH receptor antagonist activity; see also European Patent EP 0187700.
The non-peptide LHRH antagonists of the present invention comprise tetrahydro- isoquinoline derivatives not previously described by the prior art. The compounds are useful in the treating a variety of sex hormone related conditions including precocious puberty, benign prostatic hyperplasia, breast and ovarian tumors, prostate tumors, cryptorchidism, hirsutism in women, gastric motility disorders, dysmenorrhea and endometriosis.